Pathologies that involve an autoimmune response are well known. Conditions that involve damage done to tissue by a given human or animal patient's own immune system include, for example, type 1 (juvenile) diabetes, rheumatoid arthritis, multiple sclerosis, and some inflammatory conditions including, for example, psoriasis. Typically a portion of the animal's own immune system mounts an attack on an antigen of the animal's own tissue. As exemplified by the aforementioned autoimmune diseases the results can be catastrophic, ranging from the creation of a chronic albeit manageable condition like diabetes, to complete disability and premature death as often occurs with multiple sclerosis.
In addition to various diseases specifically tied to an autoimmune response, other diseases may also involve an errant immune response. Accordingly, there is profound interest in examining the etiology of various diseases to determine what, if any, role the patient's own immune response may play in the progression of the disease.
Another pathology that includes an attack on indispensable tissue by a patent's own immune system is allograft rejection following organ or tissue transplantation. Transplantation of various organs including heart, kidney, liver and lung often results in the transplant recipients' immune system attacking the transplanted tissue. To minimize allograft rejection great care is taken to match organ donors and recipients. Still, perfect matches outside of those between identical twins are virtually impossible to make. In order to manage the ensuing alloimmune response, most transplant recipients are treated with immunosuppressive compounds for the duration of their lives in order to control the autoimmune response that might otherwise destroy the transplanted organ and or tissue.
Allograft rejection is especially problematic in pulmonary transplants between individuals that are less than perfect matches for one another. It is widely believed in the field of pulmonary transplants that rejection occurs more often with lung transplants than with the transplantation of most other solid organs. In fact, the leading cause of death in lung allograft recipients is chronic rejection, known as bronchiolitis obliterans (BO) (Trulock, 1997; Westra, et al., 1990). The pathogenesis of chronic rejection is poorly understood; however, the risk of developing chronic rejection is believed to correlate with repeated acute rejection episodes.
Bronchiolitis obliterans (BO) is a form of chronic rejection that is the major impediment to long term acceptance of the lung and survival of the allograft recipient, affecting at least 60% of 5-year post lung transplant survivors. The histopathology of BO suggests that inflammation and injury response leads to a final common pathway, the development of lesions associated with small airway obliteration. Ubiquitous donor HLA antigens are believed to be the target and stimulus of the acute rejection response. However, despite newer therapeutic agents that have reduced the incidence of acute rejection, the incidence of BO is unchanged, suggesting that drug-resistant host responses to tissue-specific antigens may be involved in the chronic rejection process.
Organ rejection, in many cases, is thought to be initiated by the recognition of allogeneic (donor) major histocompatibility complex (MHC) molecules by host T lymphocytes, leading to upregulated cellular and humoral immunity. Various treatments include administering Immunosuppressive agents to reduce the severity of the immune response to the transplanted organ. Unfortunately, in many cases these therapies fail to prevent continued rejection episodes, and therefore, the ultimate goal of inducing indefinite acceptance of the allograft, known as immunologic tolerance, remains elusive.
Allogeneic MHC molecules are the stimulus and target of the immune response during rejection. Therefore, MHC-derived peptides or synthetic peptides that may be homologous to MHC antigens have been the focus of investigations attempting to induce immunological tolerance to allografts (Krensky and Clayberger, 1997; Oluwole, et al., 1993). In addition, a very recent study reports the induction of tolerance to multiple allogeneic MHC molecules in vitro by a non-polymorphic synthetic peptide derived from MHC molecules (Murphy, et al., 1999). However, none of these reports appear to have resolved the issues of allograft rejection, and, in particular, lung allograft rejection.
Since recognition of polymorphic regions of donor MHC molecules is usually the stimulus for allo-immune responses, immunological tolerance induced by peptides derived from the donor MHC may be specific to the allele of the donor MHC molecules. Accordingly, identification of proteins/peptides that are highly conserved amongst individuals and that also induce immunologic tolerance across multiple MHC alleles may be of great importance in developing effective therapies to treat patients suffering from or at risk for developing allograft rejection. However, the use of such proteins/peptides for induction of immunological tolerance to lung allografts has not been fully evaluated. Further, very few proteins/peptides that are useful for such tolerance have been reported.
Furthermore, despite the existence of different techniques to induce tolerance to solid organ allografts, such as donor specific blood transfusion, thymic injection with donor-derived APC's, or systemic immunization with peptides derived from donor MHC molecules prior to transplantation (Krensky and Clayberger, 1997), for any of these techniques to be effective the specific donor MHC molecules must be known several weeks prior to transplantation to allow sufficient time, i.e., weeks to months, for tolerance induction to develop. However, in the typical scenario only a few hours exist between the identification of a potential donor and the transplantation surgery, in most cases then there is insufficient time to induce tolerance in most transplant recipients.
Transplant recipients who already suffer from an autoimmune disease, which may have itself necessitated the need for an organ transplant may be at heighten risk for catastrophic rejection of transplanted organs. Accordingly, there is a need to identify and perhaps treat any underlying autoimmune based pathology, if not before, certainly after a transplantation. There are also various lung diseases and disorders such as Idiopathic Pulmonary Fibrosis (IPF) which are difficult to diagnose and treat and whose underlying etiology is unknown, further complicating effort to diagnose and treat them.
Clearly then, there is a need for methods that can be used to identify autoimmune diseases such as IPF and to treat or at least manage such diseases. The need is especially acute in the case of diseases where one leading treatment, lung transplantation, may itself be severely compromised by an existing pathogenic autoimmune response. Various aspects and embodiments are directed to diagnosing and treating diseases that are caused by, or aggravated by, an undesirable autoimmune response to component of the lung such as various and specific types of collagen.